EP4139327A1 - Peptid-platin-komplexe und verfahren zur verwendung davon - Google Patents

Peptid-platin-komplexe und verfahren zur verwendung davon

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Publication number
EP4139327A1
EP4139327A1 EP21792376.2A EP21792376A EP4139327A1 EP 4139327 A1 EP4139327 A1 EP 4139327A1 EP 21792376 A EP21792376 A EP 21792376A EP 4139327 A1 EP4139327 A1 EP 4139327A1
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EP
European Patent Office
Prior art keywords
peptide
platinum
complex
pharmaceutically acceptable
platinum complex
Prior art date
Legal status (The legal status is an assumption and is not a legal conclusion. Google has not performed a legal analysis and makes no representation as to the accuracy of the status listed.)
Pending
Application number
EP21792376.2A
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English (en)
French (fr)
Inventor
Mario Dipaola
Krzysztof Dziewiszek
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Oncovolution LLC
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Oncovolution LLC
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Publication date
Application filed by Oncovolution LLC filed Critical Oncovolution LLC
Publication of EP4139327A1 publication Critical patent/EP4139327A1/de
Pending legal-status Critical Current

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    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/10—Dispersions; Emulsions
    • A61K9/127—Liposomes
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/0012—Galenical forms characterised by the site of application
    • A61K9/0019—Injectable compositions; Intramuscular, intravenous, arterial, subcutaneous administration; Compositions to be administered through the skin in an invasive manner
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/08—Solutions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/14—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles
    • A61K9/19—Particulate form, e.g. powders, Processes for size reducing of pure drugs or the resulting products, Pure drug nanoparticles lyophilised, i.e. freeze-dried, solutions or dispersions
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K9/00—Medicinal preparations characterised by special physical form
    • A61K9/48—Preparations in capsules, e.g. of gelatin, of chocolate
    • A61K9/50—Microcapsules having a gas, liquid or semi-solid filling; Solid microparticles or pellets surrounded by a distinct coating layer, e.g. coated microspheres, coated drug crystals
    • A61K9/51—Nanocapsules; Nanoparticles
    • A61K9/5107—Excipients; Inactive ingredients
    • A61K9/513—Organic macromolecular compounds; Dendrimers
    • A61K9/5146—Organic macromolecular compounds; Dendrimers obtained otherwise than by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyethylene glycol, polyamines, polyanhydrides
    • A61K9/5153—Polyesters, e.g. poly(lactide-co-glycolide)
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61P—SPECIFIC THERAPEUTIC ACTIVITY OF CHEMICAL COMPOUNDS OR MEDICINAL PREPARATIONS
    • A61P35/00—Antineoplastic agents
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/06—Linear peptides containing only normal peptide links having 5 to 11 amino acids
    • C—CHEMISTRY; METALLURGY
    • C07—ORGANIC CHEMISTRY
    • C07K—PEPTIDES
    • C07K7/00—Peptides having 5 to 20 amino acids in a fully defined sequence; Derivatives thereof
    • C07K7/04—Linear peptides containing only normal peptide links
    • C07K7/08—Linear peptides containing only normal peptide links having 12 to 20 amino acids
    • A—HUMAN NECESSITIES
    • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
    • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
    • A61K38/00—Medicinal preparations containing peptides

Definitions

  • Cis- diamminedichloroplatinum (II) (cisplatin) is a clinically significant anticancer agent useful for the treatment of a broad spectrum of neoplastic diseases in humans (Loehrer et al., Ann. Int. Med.100:704-713 (1984)).
  • long-term treatment with cisplatin is limited by systemic toxicity, including emesis, nephrotoxicity, ototoxicity and neurotoxicity (Zwelling et al., “Platinum Complexes” in Pharmacologic Principles of Cancer Treatment, Ed. B. A.
  • Carboplatin is effective when used in place of cisplatin in established chemotherapeutic drug regimens and although less emetic, nephrotoxic, neurotoxic, and ototoxic than cisplatin, carboplatin has undesirable myelosuppressive properties that cisplatin does not (Go et al., J. Clin. Oncol.1999, 17(1): 409-22).
  • Oxaliplatin is a more recently developed third-generation cisplatin analog with a 1,2-diaminocyclohexane (DACH) carrier ligand which has displayed clinical activity in a variety of tumor types and is not cross-resistant with cisplatin and carboplatin.
  • DACH 1,2-diaminocyclohexane
  • Oxaliplatin acts synergistically with 5-fluorouracil (5-fluorouracil) in both 5-fluorouracil resistant and chemotherapy-naive disease and has also been evaluated as a single-agent and in combination regiments for treatment of breast, lung and prostate cancer and non-Hodgkin’s lymphoma (Misset et al., Crit Rev. Oncol. Hematol.2000, 35(2): 75-93).
  • Other platinum analogs have shown promise in clinical trials; these include NDDP (cis-bis-neodecanoato-trans-R,R-1,2-dicyclohexane platinum (II) (U.S. Patent No.
  • the invention provides peptide platinum complexes and their use to treat cancer.
  • Peptide platinum complexes according to the invention when administered to a subject, target delivery of the cytotoxic platinum to cancer cells.
  • the platinum moiety of the complex confers cytotoxicity to cancer cells intercalating into the cancer cell DNA and causing cell death.
  • the peptide(s) moiety confers specificity on the complex by directing the peptide platinum complex to cancer cells which contain a binding partner for the peptide.
  • the binding partner may be a receptor for the peptide or another peptide-recognizing entity.
  • the present invention provides a purified complex of formula (I) (a “peptide platinum complex”) as below: or pharmaceutically acceptable salts thereof, wherein [0011] R1 and R2 are independently -N(R6)2, -NH3 + , or R1 and R2 are each -NH2 and join through an C 2 -C 6 alkylene or C 3 -C 7 cycloalkylene group to form a bidentate diamine ligand; R3 is a peptide coordination ligand; R4 is a peptide coordination ligand, an inorganic coordination ligand, -Cl, -CN, - NO3,,-OH, H2O or –OC(O)R5; R5 is C 1 -C 24 alkyl; and each R6 is independently -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycl
  • Some embodiments include a purified peptide platinum complex having the formula (I): or a pharmaceutically acceptable salt thereof, wherein R1 and R2 are independently -N(R6)2, -NH3 + , or R1 and R2 are each -NH2 and join through an C 2 -C 6 alkylene or C 3 -C 7 cycloalkylene group to form a bidentate diamine ligand; R3 is a peptide ligand, with the proviso that R3 cannot be an amino acid; R4 is a peptide ligand, an inorganic ligand, -CN or –OC(O)R5, with the proviso that R4 cannot be an amino acid; R5 is C 1 -C 24 alkyl; and each R 6 is independently -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl or -aryl; R5 is C 1 -C 24 alkyl; and each R 6 is independently -H,
  • the chemotherapeutic complex comprises diaminocyclohexylcarbonato-platinate (II) (11) encapsulated into liposomes or encapsulated into biocompatible polymeric nanoparticles, such as polylacticglycolic acid (PLGA).
  • R3 and R4 are each, independently, a peptide. Any one of the peptide platinum complex as above wherein R3 and R4 are joined to form a bidentate peptide ligand. Any one of the peptide platinum complex as above wherein the peptide contains cysteine. Any one of the peptide platinum complex as above wherein the peptide contains methionine.
  • any one of the peptide platinum complex as above wherein the peptide terminal primary amino group is acylated. Any one of the peptide platinum complex as above wherein the peptide contains one or more of L-glycine, L-proline, L-serine, L-arginine, L-valine, and L-cysteine Any one of the peptide platinum complex as above wherein the peptide forms a complex with platinum via a linker. Any one of the peptide platinum complex as above wherein R1 and R2 are joined to form a bidentate diamine ligand.
  • the bidentate diamine ligand is selected from the group consisting of trans-R,R-1,2-diaminocyclohexane, trans-S,S- 1,2-diaminocyclohexane, cis-1,2-diaminocyclohexane or 1,2-ethylenediamine.
  • R4 is an inorganic ligand, -CN or -OC(O)R5; wherein R5 is C 1 -C 24 alkyl.
  • a peptide platinum complex selected from the group consisting of: a) cis-bis[AcGPSRVGGCNH2][trans-(1R,2R)-1,2-diaminocyclohexane]platinum(II), or a pharmaceutically acceptable salt thereof, said complex or salt being in purified form; b) cis-[AcGPSRVGGCNH 2 ] [trans-(1R,2R)-1,2-diaminocyclohexane]platinum(II), or a pharmaceutically acceptable salt thereof, said complex or salt being in purified form;c) cis-bis[AcGPSRVGGCNH2HCl][trans-(rac)-1,2- diaminocyclohexane]platin
  • Some embodiments include peptide platinum complex as above which further comprises an additional anticancer agent other than the peptide platinum complex as above or a pharmaceutically acceptable salt of the peptide platinum complex as above.
  • the additional anticancer agent is gemcitabine, capecitabine or 5-fluorouracil.
  • Some embodiments include a pharmaceutical composition comprising an amount of the peptide platinum complex as above or a pharmaceutically acceptable salt of the peptide platinum as above effective to treat cancer, and a pharmaceutically acceptable carrier or vehicle.
  • any one of the pharmaceutical composition as above further comprising an amount of an additional anticancer agent other than the peptide platinum complex as above or a pharmaceutically acceptable salt of the peptide platinum complex as above effective to treat cancer.
  • Some embodiments include a method for treating cancer, the method comprising administering to a subject in need thereof an amount of any one of the peptide platinum complex as above or a pharmaceutically acceptable salt of the peptide platinum complex as above, effective to treat cancer. Any one of the method as above further comprising administering to said subject an additional anticancer agent which is not the peptide platinum complex as above or the pharmaceutically acceptable salt of the peptide platinum complex as above.
  • any one of the method as above further comprising administering to said subject an additional anticancer agent which is not the peptide platinum complex as above.
  • the additional anticancer agent is gemcitabine, capecitabine or 5-fluorouracil.
  • the cancer is pancreatic cancer, colorectal cancer or mesothelioma.
  • the subject is a human.
  • kits comprising a container which contains a unit dosage form of any one of the peptide platinum complex as above or a pharmaceutically acceptable salt thereof. Any one the kit as above, further comprising a second container, the second container containing a solution for reconstitution of the peptide platinum complex.
  • any one the kit as above, wherein the solution is an aqueous solution. Any one the kit as above, wherein the aqueous solution comprises sodium chloride. Any one the kit as above, wherein the aqueous solution is a saline solution. Any one the kit as above, wherein the saline solution is phosphate buffered saline. Any one the kit as above, wherein the aqueous solution comprises dextrose. Any one the kit as above, wherein the dextrose solution is isotonic. Any one the kit as above, further comprising a second container, the second container containing an additional anticancer agent other than the peptide platinum complex as above or a pharmaceutically acceptable salt of the peptide platinum complex as above.
  • kits as above wherein the additional anticancer agent is gemcitabine, capecitabine or 5-fluorouracil. Any one the kit as above, further comprising a second container, the second container containing an antiemetic agent or a hematopoietic colony stimulating factor. Any one the kit as above, further comprising means for administering the peptide platinum complex or a pharmaceutically acceptable salt thereof to a subject.
  • Some embodiments include a method for making a platinum complex of formula (I), comprising allowing a complex of formula(II), to react with at least about 2 molar equivalents of a compound of formula (II), AcGPSRVGGCNH 2 or AcGPSRVGGCD
  • R1 and R2 are independently -N(R6)2, -NH3 + , or R1 and R2 are each -NH2 and join through an C 2 -C 6 alkylene or C 3 -C 7 cycloalkylene group to form a bidentate diamine ligand;
  • R 3 is a peptide ligand, with the proviso that R 3 cannot be an amino acid;
  • R 4 is a peptide ligand, an inorganic ligand, -CN or –OC(O)R 5 , with the proviso that R 4 cannot be an amino acid;
  • R5 is C 1 -C 24 alkyl; each R6 is independently -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl or -aryl; and halo is -F, -Cl, -Br, -I or -At.
  • R3 is a peptide.
  • R4 is a peptide.
  • R3 and R4 are each independently a peptide.
  • R 1 and R 2 join to form a bidentate diamine ligand.
  • the bidentate diamine ligand is trans-R,R-1,2-diaminocyclohexane, trans-S,S-1,2-diaminocyclohexane, cis- 1,2-diaminocyclohexane or 1,2-ethylenediamine.
  • the invention also includes pharmaceutical compositions that comprise an amount of a peptide platinum complex effective to treat cancer, and a pharmaceutically acceptable carrier, vehicle or excipient(s).
  • the compositions are useful for treating cancer.
  • the invention includes a peptide platinum complex when provided as a pharmaceutically acceptable salt.
  • FIG.1 shows a dose response curve for cell killing of the human skin malignant melanoma cell line, A375 using Onco-001
  • Fig.2 shows a dose response curve for cell killing of the human skin malignant melanoma cell line, A375 using Onco-003
  • Fig.3 shows a dose response curve for cell killing of the human skin malignant melanoma cell line, A375 using Onco-005
  • Fig.4 shows a dose response curve for cell killing of the BEL-7402 cells using Doxorubicin.
  • This invention provides a novel class of coordination compounds, or more specifically peptide platinum complexes, according to Formula I, as set forth below: and pharmaceutically acceptable salts, solvates and hydrates thereof, wherein R 1 and R 2 are independently -N(R 6 ) 2 , -NH 3 + , or R 1 and R 2 are each -NH 2 and join through an C 2 -C 6 alkylene or C 3 -C 7 cycloalkylene group to form a bidentate diamine ligand; R3 is a peptide ligand R4 is a peptide ligand, an inorganic ligand, -CN or –OC(O)R5, -Cl, -CN, -NO3, - OH, H 2 O; R3 and R4 can also be the same peptide but containing two functional groups, including an amine, a carboxy or sulfhydryl, that can coordinate with Pt R 5
  • C 1 -C 6 alkyl refers to a straight or branched chain, saturated or unsaturated hydrocarbon having from 1 to 6 carbon atoms.
  • Representative C 1 -C 6 alkyl groups include, but are not limited to methyl, ethyl, propyl, isopropyl, butyl, sec-butyl, tert-buty, pentyl, isopentyl, neopentyl, hexyl, isohexyl, neohexyl, ethylenyl, propylenyl, 1- butenyl, 2-butenyl, 1-pentenyl, 2-pentenyl, 1-hexenyl, 2-hexenyl, 3-hexenyl, acetylenyl, pentynyl, 1-butynyl, 2-butynyl, 1-pentynyl, 2-pentynyl, 1-hexynyl, 2-hexynyl and 3-hexynyl.
  • alkoxy refers to a –O-(C 1 -C 6 alkyl) group.
  • Representative alkoxy groups include, but are not limited to methoxy, ethyl, propoxy, isopropoxy, butoxy, sec-butoxy, tert-butoxy, pentyloxy, isopentyloxy, neopentyloxy, hexyloxy, isohexyloxy and neohexyloxy.
  • C 1 -C 24 alkyl refers to a straight chain or branched, saturated or unsaturated hydrocarbon having from 1 to 24 carbon atoms.
  • Representative C1- C24 alkyl groups include, but are not limited to, methyl, ethyl, propyl, butyl, pentyl, hexyl, heptyl, octyl, nonyl, decyl, undecyl, dodecyl, isopropyl, isobutyl, sec-butyl and tert-butyl, isopentyl, neopentyl, isohexyl, neohexyl, isoheptyl, neoheptyl, isooctyl, neooctyl, isononyl, neononyl, isodecyl, neodecyl, myristoyl, oleoyl, palmitoyl, stearoyl, lauroyl and caproyl.
  • a C 1 -C 24 alkyl group can be unsubstituted or optionally substituted with one or more -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl, -alkoxy, -aryl, -heterocyclic, -halo, -CN, -COOH, -COOR 6 , - OC(O)R6, -NH2, -C(O)R6, -CHO, -NHR6, N(R6)2, -NHC(O)R6 or -C(O)NHR6 groups wherein R6 is -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl or -aryl.
  • alkylcarboxylate or alkylcarboxylato refers to a group having the structure: wherein R 5 is a C 1 -C 24 alkyl group.
  • C 2 -C 6 alkylene refers to a divalent, straight or branched chain, saturated hydrocarbon having from 2 to 6 carbon atoms.
  • aryl refers to a phenyl group or a naphthyl group.
  • bidentate diamine ligand refers to ligands of the general formula: wherein X is a C 2 -C 6 alkylene or C 3 -C 7 cycloalkylene group which links the two NH2 groups. Such a bidentate ligand coordinates to the platinum via the two NH2 groups, each of which occupies a separate coordination site on the metal.
  • a bidentate diamine ligand can be chiral or achiral.
  • Representative bidentate diamine ligands include, but are not limited to, trans-R,R- 1,2-diaminocyclohexane, trans-S,S-1,2-diaminocyclohexane, cis-1,2-diaminocyclohexane and 1,2-ethylenediamine.
  • linker is used to refer to a covalent means of connecting a peptide and a platinum moiety. A linker serves not only a connecting function but also minimizes steric hindrance among the platinum peptide complex and the target as the peptide binds its target.
  • the linker can be designed in a such a manner to facilitate dissociation of the peptide from the platinum moiety, once the construct has been internalized into the cell.
  • a succinyl or a glutaryl linker will result in release through esterases/amidases action (Karampelas et al., Bioconjugate Chem., 2014, 25, 813-823; Sun et al., Curr. Drug Delivery 2011, 8, 2-10), while using para-amino benzyl alcohol or a linker with an oxime bond will yield release upon 1,6 elimination or hydrolysis in acidic pH, respectively (Zhang et al. , Eur. J. Med.
  • C 3 -C 7 cycloalkyl as used herein is a 3-, 4- 5-, 6- or 7-membered saturated or unsaturated non-aromatic carbocyclic ring.
  • Representative cycloalkyls include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl, cyclopentadienyl, cyclohexyl, cyclohexenyl, cycloheptyl, cycloheptanyl, 1,3-cyclohexadienyl, -1,4-cyclohexadienyl, -1,3- cycloheptadienyl, and -1,3,5-cycloheptatrienyl.
  • C 3 -C 7 cycloalkylene refers to a 3-, 4- 5-, 6- or 7-membered divalent, saturated or unsaturated non-aromatic carbocyclic ring.
  • Cisplatin, PtCl2(NH3)2 is a coordination complex of platinum(II) with two chloride and two ammonia ligands. It is a commonly-used anticancer drug and has the following molecular structure.
  • the term “coordinate complex” refers to a molecule which contains a central atom or ion, which is usually metallic and is called the coordination center, and a surrounding array of bound molecules or ions, that are in turn known as ligands or complexing agents. Lawrance, Geoffrey A. (2010).
  • a coordination complex whose center is a metal atom is called a metal complex.
  • the central atom or ion, together with all ligands, comprise the coordination sphere.
  • a coordination complex is the product of a Lewis acid-base reaction in which neutral molecules or anions (called ligands) bond to a central metal atom (or ion) by coordinate covalent bonds.
  • Ligands are Lewis bases - they contain at least one pair of electrons to donate to a metal atom/ion.
  • Ligands are also called complexing agents.
  • Metal atoms/ions are Lewis acids - they can accept pairs of electrons from Lewis bases.
  • the donor atom Within a ligand, the atom that is directly bonded to the metal atom/ion is called the donor atom.
  • a coordinate covalent bond is a covalent bond in which one atom (i.e., the donor atom) supplies both electrons. This type of bonding is different from a normal covalent bond in which each atom supplies one electron. If the coordination complex carries a net charge, the complex is called a complex ion. Compounds that contain a coordination complex are called coordination compounds. Coordination compounds and complexes are distinct chemical species - their properties and behavior are different from the metal atom/ion and ligands from which they are composed. Coordination refers to the "coordinate covalent bonds" (dipolar bonds) between the ligands and the central atom.
  • the term “functional group” refers to ion or molecule that binds to the central metal atom
  • the term “halo” as used herein refers to –F, -Cl, -Br or –I.
  • the term “inorganic ligand” as used herein refers to a ligand that does not comprise a carbon-containing organic functional group. Representative examples of inorganic ligands include, but are not limited to, Cl-, Br-, I-, F-, NO3-, OH-, H2O, HCO3- and HSO4-.
  • peptide refers to an amino acid oligomer which is composed of from 5 up to and including 30 amino acid residues, including all lengths between 5 and 30, for example 7 to 25 residues, 8 to 20 residues, 9 to 18 residues, and 10 to 15 residues, and all peptide lengths between these ranges.
  • Peptide moiety refers to a single peptide, a multimer of the same peptide or multiple and different peptides.
  • Peptide ligand refers to a peptide molecule coordinating with platinum.
  • peptide platinum complex as used herein, refers to a tetracoordinate platinum complex of formula (I) as described herein.
  • a peptide platinum complex is in purified form.
  • purified means that when isolated (e.g., from other components of a synthetic organic chemical reaction mixture), the isolate contains at least 50%, at least 55%, at least 60%, at least 65%, at least 70%, at least 75%, at least 80%, at least 85%, at least 90%, at least 95% or at least 98% of a peptide platinum complex of the invention by weight of the isolate. In a preferred embodiment, the isolate contains at least 95% of a peptide platinum complex of the invention by weight of the isolate.
  • DACH 1,2-diaminocyclohexane
  • ACN acetonitrile
  • EtOH ethyl alcohol
  • HPLC high pressure liquid chromatography
  • peptide is a short chain of single amino acids linked by amide (peptide) bonds.
  • any references herein to a product by trade name is intended to include at least the corresponding generic product/name currently associated with the trade name and equivalent and similar products
  • PEPTIDE PLATINUM COMPLEXES [0051]
  • the peptide platinum complexes of the invention are tetracoordinate platinum (II) complexes in which two adjacent coordination sites (represented by R1 and R2 in Formula I) are independently occupied by an amine or an ammine (NH3 + ) ligand, or alternately, R1 and R 2 together represent a single bidentate diamine ligand.
  • the third coordination site (R 3 of Formula I) is occupied by a peptide ligand, while the final coordination site (R4 of Formula I) can be occupied by a peptide ligand, an inorganic ligand or an organic ligand.
  • the present invention further encompasses pharmaceutically acceptable salts of the peptide platinum complexes of the invention, including both organic and inorganic salts of the peptide platinum complexes of the invention.
  • the peptide platinum complexes of the invention contain at least one amino group, and accordingly, it is possible to form acid addition salts with an amino group of a peptide platinum complex of the invention.
  • Preferred salts include, but are not limited, to sulfate, citrate, acetate, oxalate, chloride, bromide, iodide, nitrate, bisulfate, phosphate, acid phosphate, isonicotinate, lactate, salicylate, acid citrate, tartrate, oleate, tannate, pantothenate, bitartrate, ascorbate, succinate, maleate, gentisinate, fumarate, gluconate, glucaronate, saccharate, formate, benzoate, glutamate, methanesulfonate, ethanesulfonate, benzenesulfonate, p-toluenesulfonate, and pamoate (i.e., 1,1’-methylene-bis-(2-hydroxy-3-naphthoate)) salts.
  • pamoate i.e., 1,1’-methylene-bis-(2-hydroxy
  • a pharmaceutically acceptable salt may involve the inclusion of another molecule such as an acetate ion, a succinate ion or other counterion.
  • the counterion can be any organic or inorganic moiety that stabilizes a charge, which may be present on a peptide platinum complex of the invention.
  • a pharmaceutically acceptable salt may have more than one charged atom in its structure. In instances where multiple charged atoms are part of the pharmaceutically acceptable salt, said salt can have multiple counterions.
  • a pharmaceutically acceptable salt of a peptide platinum complex can have one or more charged atoms and/or one or more counterions.
  • AMINE/AMMINE LIGANDS [0053] R 1 and R 2 are independently an amine or ammine (NH 3 + ) ligand.
  • the amine ligands of the invention are represented by the formula -N(R6)2 where each R6 is independently -H, -C 1 -C 6 alkyl, -C 3 -C 7 cycloalkyl or -aryl.
  • R1 and R 2 are each -NH 2 and join through a C 2 -C 6 alkylene or C 3 -C 7 cycloalkylene group to form a bidentate diamine ligand.
  • Bidentate diamine ligands useful in the invention include, but are not limited to, trans-R,R-1,2-diaminocyclohexane, trans-S,S-1,2-diaminocyclohexane, cis-1,2-diaminocyclohexane and 1,2-ethylenediamine.
  • a peptide platinum complex comprises a bidentate diamine ligand.
  • a peptide platinum complex comprises a bidentate 1,2- ethylenediamine ligand.
  • a peptide platinum complex comprises a bidentate 1,2-diaminocyclohexane ligand.
  • a peptide platinum complex comprises a bidentate trans-R,R-1,2-diaminocyclohexane ligand.
  • PEPTIDE LIGANDS Peptides are useful herein as addition moieties to platinum to form the peptide platinum complexes of the invention, which complexes comprise a tetracoordinate platinum complex having at least one peptide ligand.
  • a peptide useful according to the invention will be capable of binding to an antigen present on the surface or within the cancer cell. Such a peptide will possess a high degree of specificity for its target.
  • the affinity of a given peptide for its target can be assessed using a binding assay by means of a radioassay, ELISA, or surface plasmon resonance (SPR) and will have a binding affinity in the range of high micromolar to sub- nanomolar. Specificity of a given peptide can be assessed using a cell-based assay, ELISA or SPR.
  • a peptide useful according to the invention is composed of amino acids and therefore each peptide has an amino group and a carboxy group, or possibly a sulfhydryl, from which to connect the peptide to the platinum compound.
  • a peptide useful according to the invention for targeting breast cancer may contain or consist of the sequence CRXXRXXXC (where X can be any amino acid other than C, R, W or Y; SEQ ID NO: 1), RGX1PAYX2GRFL (where X1 can be D or E and X2 can be Q or N; SEQ ID NO: 2) or PXLNVSP (where X is any amino acid, except for C, W and Y; SEQ ID NO: 3).
  • a peptide for targeting melanoma may contain or consist of the sequence motif PRP, WRP and/or S/ThXh(S/T)WXPP (where S/T implies that either will work, h represents a hydrophobic amino acid, such as I, L, A or V and X can be any except C and W; SEQ ID NOs: 151, 152, 153 and 154 ).
  • a tumor targeting peptide may contain or consist of the following consensus sequence: PXIXIT (where X can be any amino acid, except C, Y and W; SEQ ID NO: 4).
  • a cancer targeting peptide will contain or consist of the consensus sequence VD/GLPE/THXX (where D/G implies either D or G and similarly for E/T; X can be any amino acid except for C, W and Y; SEQ ID NOs: 155, 156, 157 and 158).
  • a targeting peptide for lung cancer may contain or consist of the sequence XPWXEXXYX (where X is any amino acid except for W, Y and C; SEQ ID NO: 5). [0061] See, for example, targeting peptides set forth in the following citations and Table 1.
  • Table 1 List of Targeting (homing) peptides to various cancer targets Additional peptides, and their properties are described in Le Joncour V1, Laakkonen, Bioorg Med Chem.2018 Jun 1;26(10):2797-2806. doi: 10.1016/j.bmc.2017.08.052. Epub 2017 Sep 1, and are set forth in Table 2:.. Table 2 Previously Characterized Targeting peptides Key: n, peptide sequence based on the natural ligand; s, synthetic sequence (isolated for instance from phage displayed peptides libraries); X in a sequence means any amino acid residue, ? means that the exact targeted protein/receptor is unknown.
  • SSTR somatostatin receptor
  • GRPR gastrin releasing peptide receptor
  • PSAP presenilin-associated protein
  • CXCR4 stromal-derived factor receptor
  • pHLIP pH low insertion peptide
  • ELP elastin-like peptide
  • x-MSH x-melanocyte-stimulating hormone
  • MC1R melanocortin 1 receptor
  • GZP granzyme B peptide
  • APN CD13
  • Abu L-x-amino-n-butyric acid
  • MMP metalloprotease
  • VEGFR2 vascular endothelial growth factor receptor 2
  • p32 replication protein A
  • NRP-1 neuropilin receptor-1
  • pen penetratin
  • TAM tumor-associated macrophage
  • MDGI mammary-derived growth inhibitor
  • LRP-1 low density lipoprotein receptor-related protein-1.
  • Peptide ligands useful in the present invention include, but are not limited to, natural and synthetic peptides with linear and cyclic structure. Peptides of the invention are composed of either natural or synthetic amino acids, which are described in Lehninger Principles of Biochemistry by David L. Nelson and Michael M. Cox 7th ed., VetBooks, W. H. Freeman and Company, New York. [0063] In one embodiment, a peptide platinum complex has a single peptide ligand.
  • a peptide platinum complex has first and second peptide ligands, which may be the same or different.
  • peptides with a single functional group that can ligate with the platinum then two peptides, whether the same or different, are likely to coordinate, if there is no steric hindrance between the two peptides.
  • a single peptide ligand is attached to two platinum moieties.
  • one peptide platinum complex has one peptide ligand, which is attached to the same platinum moiety.
  • the peptide ligand is connecting to platinum moiety through a carboxylic or an amino group.
  • the peptide ligand has the carboxylic group blocked and connects to the platinum moiety exclusively through an amino group.
  • the peptide ligand has the amino group blocked and connects to the platinum moiety exclusively through a carboxylic group.
  • the peptide ligand has the amino group blocked and connects to the platinum moiety exclusively through two carboxylic groups of the same peptide.
  • the peptide ligand is connected to the platinum moiety through a carboxylic, amino or a thio group.
  • the amino group is blocked, and the peptide ligand is connected to the platinum moiety exclusively through a thio group. Coordination of peptides to platinum can take place through the amine, the sulfhydryl or the carboxy group.
  • peptide platinum complexes can also comprise non-amino and/or non-peptide ligands.
  • Additional ligands useful according to the invention include, but are not limited to, antibodies, antibody fragments containing an antibody variable region composed of two VH and two VL chains, and single domain antibodies, such as a VH and/or a VL.
  • Peptide platinum complexes of formula (I) can be prepared via the synthetic procedure outlined below in Scheme 1. It will be apparent to one skilled in the art how to prepare the scope of the peptide platinum complexes of the invention by choice of proper and relevant starting materials, synthetic intermediates and reagents.
  • Scheme 1 Formula 2 Formula 3
  • Formula 4 Formula 6
  • Formula 7 [0078] In a typical procedure, diaminodichloroplatinum complex of formula 2 is treated with silver sulfate and water to provide the intermediate diamino sulfatoplatinum (II) monohydrate of formula 3.
  • Intermediate 3 can then be reacted with a stoichiometric excess of a reactive peptide of formula 4, to provide the diamino-bis-peptide platinum complex of diaminocyclohexane]diiodoplatinum(II) formula 6.
  • intermediate 3 instead of reacting intermediate 3 with a stoichiometric excess of a single peptide, intermediate 3 may be reacted simultaneously with one equivalent each of two different peptides in order to provide a peptide platinum complex having two different peptide ligands.
  • the complex of formula 3 can alternately be reacted with a sub-stoichiometric amount of a peptide, such as 4, in the presence of an excess of another reactive ligand, such as the alkali metal salt of an inorganic ligand or the alkali metal salt of an alkylcarboxylate 5, to yield the platinum complex of formula 7, which then contains both peptide and non-peptide ligation.
  • a sub-stoichiometric amount of a peptide such as 4
  • another reactive ligand such as the alkali metal salt of an inorganic ligand or the alkali metal salt of an alkylcarboxylate 5
  • peptide platinum complexes of formula (I) can be prepared via the synthetic procedure outlined below in Scheme 2.
  • Scheme 2 Formula 5 Formula 9 Formula 2 Formula 9 Formula 6
  • two equivalents of the peptide of formula 5 are reacted with two equivalents of AgNO 3 to provide two equivalents of the peptide of formula 9.
  • Two equivalents of peptide of formula 9 are then reacted with one equivalent of platinum complex 2 in chloroform to yield the diamino-bis-peptide platinum complex of formula 6.
  • the generic bidentate platinum complex 2 is cis-[trans-(1R,2R)-1,2-diaminocyclohexane]diiodoplatinum(II) (10)
  • the generic sodium salt of peptide 5 is the sodium salt of AcGPSRVGGCNH2Na (SEQ ID NO: 145) (13)
  • the complex formed of complex 10 and silver complex 9 is cis-bis[AcGPSRVGGCNH 2 ][trans- (1R,2R)-1,2-diaminocyclohexane]platinum(II), (14).
  • peptide platinum complex is cis- bis[AcGPSRVGGCNH2]trans-(1R,2R)-1,2-diaminocyclohexane]platinum(II).
  • the peptide platinum complexes are in purified form.
  • the present invention also relates to methods for making a compound of formula (I).
  • the invention relates to a method making a compound of formula (I), comprising allowing a complex of formula (II), to react with at least about 2 molar equivalents of a compound of formula (III), peptide ligands (R3 and R4) or -CN or –OC(O)R, -NO3, -OH, H2O, -CO3 (III) where halo is -F, -Cl, -Br, -I or -At; and R1, R2, R3, R4, X 1 and X 2 are as defined above. [0090] In one embodiment, the invention relates to a method for making a compound of formula (I) where R3 is a peptide.
  • the invention relates to a method for making a compound of formula (I) where R4 is a peptide.
  • the invention relates to a method for making a compound of formula (I) where R 3 and R 4 are each independently peptides
  • the invention relates to a method for making a compound of formula (I) where R1 and R2 join to form a bidentate diamine ligand.
  • the invention relates to a method for making a compound of formula (I) where R 1 and R 2 join to form a bidentate diamine ligand and R 3 and R 4 join to form a bidentate peptide ligand.
  • the invention relates to a method for making a compound of formula (I) where R 1 and R 2 join to form a bidentate diamine ligand and the bidentate diamine ligand is trans-R,R-1,2-diaminocyclohexane, trans-S,S-1,2-diaminocyclohexane, cis-1,2-diaminocyclohexane or 1,2-ethylenediamine.
  • the invention relates to a method for making a compound of formula (I) where R 1 and R 2 join to form trans-R,R-1,2-diaminocyclohexane, and R 3 and R4 are each AcGPSRVGGCNH2 (Onco-001; SEQ ID NO: 145) (14).
  • a dose response curve for cell killing of the human skin malignant melanoma cell line, A375, is shown as Figure 1.
  • the invention relates to a method for making a compound of formula (I) where R1 and R2 join to form trans-R,R-1,2-diaminocyclohexane, and R 3 and R 4 are joined by the bidentate peptide: AcGPSRVGGCD (Onco-003; SEQ ID NO: 146) (15).
  • the dose dependent cell killing of Onco-003, using A375 cells, is displayed in Figure 2.
  • the invention relates to a method for making a compound of formula (I) where R 1 and R 2 join to form trans-R,R-1,2-diaminocyclohexane, and R 3 and R4 are joined by the bidentate peptide, defined in Formula 10, below:
  • one equivalent of formula 10 is linked to 3 equivalents of formula (I) where R 1 and R 2 join to form trans-R,R-1,2-diaminocyclohexane.
  • the invention relates to a method for making a compound of formula (I) where R1 and R2 join to form trans-R,R-1,2-diaminocyclohexane, and R 3 and R 4 are joined by the peptide: Ac-GPSRVGGCD (structure provided, belowSEQ ID NO: 146).
  • the peptide complex as displayed below is comprised of the peptide with sequence of AcGPSRVGGCXNH 2 (SEQ ID NO: 147), where X is gamma carboxy-glutamic acid (formula 11, Onco-005).
  • the two carboxylic moieties of the gamma carboxy-glutamic acid on each peptide coordinate with R3 and R 4 in formula (I), resulting in three equivalent of formula (I) with one equivalent of formula 11, with structure shown below.
  • Dose dependent cell killing of Onco-005 (15), using A375 cells, is displayed in Figure 3, below.
  • platinum (II)-peptide conjugates specific for different types of tumor are shown below.
  • Example of a platinum (II) – peptide conjugate specific for breast cancer Example of a platinum (II) – peptide conjugate specific for lung cancer
  • Example of a platinum (II) – peptide conjugate specific for prostate cancer Example of a platinum (II) – peptide conjugate specific for sarcoma [0103] While none of these platinum-peptide conjugate examples, provided above, against breast, lung, prostate and sarcoma cancers have synthesized and tested either in-vitro or in-vivo, it is, nonetheless, predicted that the anti-cancer activity of these is going to be comparable to the anti-melanoma platinum (II)-peptide conjugates (Onco-003, Onco-005), therefore displaying EC50 values ranging between 0.01 ⁇ M and 100 ⁇ M.
  • the present invention provides a pharmaceutical composition comprised by an effective amount of the active compound and a pharmaceutically acceptable carrier or vehicle.
  • the pharmaceutical compositions are suitable for human or veterinary administration.
  • the pharmaceutical compositions of the present invention can be in any form that allows for the composition to be administered to a subject including, but not limited to a human, mammal, or non-human animal, such as a cow, horse, sheep, pig, fowl, cat, dog, mouse, rat, rabbit, guinea pig, etc., and is more preferably a mammal, and most preferably a human.
  • compositions of the invention can be in the form of a solid, liquid or gas (aerosol).
  • routes of administration may include, without limitation, oral, topical, parenteral, sublingual, rectal, vaginal, ocular, and intranasal.
  • Parenteral administration includes subcutaneous injections, intravenous, intramuscular, intraperitoneal, intrapleural, intrasternal injection or infusion techniques.
  • the compositions are administered parenterally, most preferably intravenously.
  • Pharmaceutical compositions of the invention can be formulated to allow a compound of the invention to be bioavailable upon administration of the composition to a subject.
  • compositions can take the form of one or more dosage units, where for example, a tablet can be a single dosage unit, and a container of a compound of the invention in aerosol form can hold a plurality of dosage units.
  • Materials used in preparing the pharmaceutical compositions can be non-toxic in the amounts used. It will be evident to those of ordinary skill in the art that the optimal dosage of the active ingredient(s) in the pharmaceutical composition will depend on a variety of factors. Relevant factors include, without limitation, the type of subject (e.g., human), the overall health of the subject, the type of cancer the subject is in need of treatment of, the use of the composition as part of a multi-drug regimen, the particular form of the compound of the invention, the manner of administration, and the composition employed.
  • the pharmaceutically acceptable carrier or vehicle may be particulate, so that the compositions are, for example, in tablet or powder form.
  • the carrier(s) can be liquid, with the compositions being, for example, an oral syrup or injectable liquid.
  • the carrier(s) can be gaseous, so as to provide an aerosol composition useful in, e.g., inhalatory administration.
  • the composition may be intended for oral administration, and if so, the composition is preferably in solid or liquid form, where semi-solid, semi-liquid, suspension and gel forms are included within the forms considered herein as either solid or liquid.
  • the composition can be formulated into a powder, granule, compressed tablet, pill, capsule, chewing gum, wafer or the like form.
  • a solid composition typically contains one or more inert diluents.
  • binders such as ethyl cellulose, carboxymethylcellulose, microcrystalline cellulose, or gelatin
  • excipients such as starch, lactose or dextrins, disintegrating agents such as alginic acid, sodium alginate, Primogel, corn starch and the like
  • lubricants such as magnesium stearate or Sterotex
  • glidants such as colloidal silicon dioxide
  • sweetening agents such as sucrose or saccharin, a flavoring agent such as peppermint, methyl salicylate or orange flavoring, and a coloring agent.
  • the pharmaceutical composition when in the form of a capsule, e.g., a gelatin capsule, it can contain, in addition to materials of the above type, a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
  • a liquid carrier such as polyethylene glycol, cyclodextrin or a fatty oil.
  • the pharmaceutical composition can be in the form of a liquid, e.g., an elixir, syrup, solution, emulsion or suspension.
  • the liquid can be useful for oral administration or for delivery by injection.
  • a composition can comprise one or more of a sweetening agent, preservatives, dye/colorant and flavor enhancer.
  • liquid compositions of the invention can also include one or more of the following: sterile diluents such as water for injection, saline solution, preferably physiological saline, Ringer’s solution, isotonic sodium chloride, fixed oils such as synthetic mono or digylcerides which can serve as the solvent or suspending medium, polyethylene glycols, glycerin, cyclodextrin, propylene glycol or other solvents; antibacterial agents such as benzyl alcohol or methyl paraben; antioxidants such as ascorbic acid or sodium bisulfite; chelating agents such as ethylenediaminetetraacetic acid; buffers such as acetates, citrates or phosphates and agents for the adjustment of tonicity
  • a parenteral composition can be enclosed in ampoule, a disposable syringe or a multiple-dose vial made of glass, plastic or other material.
  • Physiological saline is a preferred adjuvant.
  • An injectable composition is preferably sterile.
  • the amount of the compound of the invention that is effective in the treatment of a particular disorder or condition will depend on the nature of the disorder or condition, and can be determined by standard clinical techniques. In addition, in vitro or in vivo assays can optionally be employed to help identify optimal dosage ranges. The precise dose to be employed in the compositions will also depend on the route of administration, and the seriousness of the disease or disorder, and should be decided according to the judgment of the practitioner and each patient’s circumstances.
  • the pharmaceutical compositions comprise an effective amount of a compound of the invention such that a suitable dosage will be obtained. Typically, this amount is at least 0.01% of a compound of the invention by weight of the composition. When intended for oral administration, this amount can be varied to be between 0.1% and 80% by weight of the composition. Preferred oral compositions can comprise from between 4% and 50% of the compound of the invention by weight of the composition. Preferred compositions of the present invention are prepared so that a parenteral dosage unit contains from between 0.01% and 2% by weight of the compound of the invention. [0116] The compounds of the invention can be administered in a single dose or in multiple doses. [0117] In one embodiment, the compounds of the invention are administered in multiple doses.
  • the compounds are administered with a frequency and in an amount sufficient to treat the condition.
  • the frequency of administration ranges from once a day up to about once every eight weeks. In another embodiment, the frequency of administration ranges from about once a week up to about once every six weeks. In another embodiment, the frequency of administration ranges from about once every three weeks up to about once every four weeks.
  • the dosage of a compound of the invention administered to a subject is in the range of 0.1 to 50 mg/kg, and more typically in the range of 0.1 mg/kg to 100 mg/kg, of the subject’s body weight.
  • the dosage administered to a subject is in the range of 0.1 mg/kg to 50 mg/kg, or 1 mg/kg to 50 mg/kg, of the subject’s body weight, more preferably in the range of 0.1 mg/kg to 25 mg/kg, or 1 mg/kg to 25 mg/kg, of the subject’s body weight.
  • the compounds of the invention can be administered by any convenient route, for example by infusion or bolus injection, by absorption through epithelial or mucocutaneous linings (e.g., oral mucosa, rectal and intestinal mucosa, etc.). Administration can be systemic or local.
  • compositions of the invention may include, but are not limited to, oral administration and parenteral administration; parenteral administration including, but not limited to, intradermal, intramuscular, intraperitoneal, intravenous, subcutaneous; intranasal, epidural, sublingual, intranasal, intracerebral, intraventricular, intrathecal, intravaginal, transdermal, rectally, by inhalation, or topically to the ears, nose, eyes, or skin.
  • the preferred mode of administration is left to the discretion of the practitioner and will depend in-part upon the site of the medical condition (such as the site of cancer, a cancerous tumor or a pre-cancerous condition).
  • the compounds of the invention are administered parenterally.
  • the compounds of the invention are administered intravenously.
  • administration can be by direct injection at the site (or former site) of a cancer, tumor, or precancerous tissue.
  • it can be desirable to introduce one or more compounds of the invention into the central nervous system by any suitable route, including intraventricular and intrathecal injection.
  • Intraventricular injection can be facilitated by an intraventricular catheter, for example, attached to a reservoir, such as an Ommaya reservoir.
  • Pulmonary administration can also be employed, e.g., by use of an inhaler or nebulizer, and formulation with an aerosolizing agent, or via perfusion in a fluorocarbon or synthetic pulmonary surfactant.
  • the compounds of the invention can be formulated as a suppository, with traditional binders and carriers such as triglycerides.
  • the compounds of the invention can be delivered in a controlled release system. In one embodiment, a pump can be used (see Langer, supra; Sefton, CRC Crit. Ref. Biomed.
  • polymeric materials can be used (see Medical Applications of Controlled Release, Langer and Wise (eds.), CRC Pres., Boca Raton, Florida (1974); Controlled Drug Bioavailability, Drug Product Design and Performance, Smolen and Ball (eds.), Wiley, New York (1984); Ranger and Peppas, J. Macromol. Sci. Rev. Macromol. Chem.23:61 (1983); see also Levy et al., Science 228:190 (1985); During et al., Ann.
  • a controlled-release system can be placed in proximity of the target of the compounds of the invention, e.g., the brain, thus requiring only a fraction of the systemic dose (see, e.g., Goodson, in Medical Applications of Controlled Release, supra, vol.2, pp.115-138 (1984)).
  • Other controlled-release systems discussed in the review by Langer discussed in the review by Langer (Science 249:1527-1533 (1990)) can be used.
  • carrier refers to a diluent, adjuvant or excipient, with which a compound of the invention is administered.
  • Such pharmaceutical carriers can be liquids, such as water and oils, including those of petroleum, animal, vegetable or synthetic origin, such as peanut oil, soybean oil, mineral oil, sesame oil and the like.
  • the carriers can be saline, gum acacia, gelatin, starch paste, talc, keratin, colloidal silica, urea, and the like.
  • auxiliary, stabilizing, thickening, lubricating and coloring agents can be used.
  • the compounds of the invention and pharmaceutically acceptable carriers when administered to a subject, are sterile. Water is a preferred carrier when the compound of the invention is administered intravenously. Saline solutions and aqueous dextrose and glycerol solutions can also be employed as liquid carriers, particularly for injectable solutions.
  • Suitable pharmaceutical carriers also include excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • excipients such as starch, glucose, lactose, sucrose, gelatin, malt, rice, flour, chalk, silica gel, sodium stearate, glycerol monostearate, talc, sodium chloride, dried skim milk, glycerol, propylene, glycol, water, ethanol and the like.
  • the present compositions if desired, can also contain minor amounts of wetting or emulsifying agents, or pH buffering agents.
  • compositions can take the form of solutions, suspensions, emulsion, tablets, pills, pellets, capsules, capsules containing liquids, powders, sustained-release formulations, suppositories, emulsions, aerosols, sprays, suspensions, or any other form suitable for use.
  • the pharmaceutically acceptable carrier is a capsule (see e.g., U.S. Patent No.5,698,155).
  • suitable pharmaceutical carriers are described in “Remington’s Pharmaceutical Sciences” by E.W. Martin.
  • Sustained or directed release compositions that can be formulated can include, but are not limited to, the liposomal (lipid nanoparticles), polymeric nanoparticles, prepared with PLGA and other biocompatible polymers, and micellar platinum complexes of the invention, virus-like particles and other formulations where a peptide platinum complex of the invention is protected with differentially degradable coatings, e.g., by microencapsulation, multiple coatings, etc. It is also possible to freeze-dry the compositions and use the lyophilizates obtained, for example, for the preparation of products for injection. [0128] In a preferred embodiment, the peptide platinum complexes of the invention are delivered in solution.
  • the solution is containing isotonic solution of dextrose.
  • the compounds of the invention are formulated in accordance with routine procedures as a pharmaceutical composition adapted for intravenous administration to animals, particularly human beings.
  • the carriers or vehicles for intravenous administration are sterile isotonic aqueous buffer solutions.
  • the compositions can also include a solubilizing agent.
  • Compositions for intravenous administration can optionally comprise a local anesthetic such as lignocaine to ease pain at the site of the injection.
  • the ingredients are supplied either separately or mixed together in unit dosage form, for example, as a dry lyophilized powder or water free concentrate in a hermetically sealed container such as an ampoule or sachette indicating the quantity of active agent.
  • a compound of the invention is to be administered by infusion, it can be dispensed, for example, with an infusion bottle containing sterile pharmaceutical grade water or saline.
  • an ampoule of sterile water for injection or saline can be provided so that the ingredients can be mixed prior to administration.
  • compositions for oral delivery can be in the form of tablets, lozenges, aqueous or oily suspensions, granules, powders, emulsions, capsules, syrups, or elixirs, for example.
  • Orally administered compositions can contain one or more optionally agents, for example, sweetening agents such as fructose, aspartame or saccharin; flavoring agents such as peppermint, oil of wintergreen, or cherry; coloring agents; and preserving agents, to provide a pharmaceutically palatable preparation.
  • sweetening agents such as fructose, aspartame or saccharin
  • flavoring agents such as peppermint, oil of wintergreen, or cherry
  • coloring agents such as peppermint, oil of wintergreen, or cherry
  • preserving agents to provide a pharmaceutically palatable preparation.
  • the compositions can be coated to delay disintegration and absorption in the gastrointestinal tract thereby providing a sustained action over an extended period of time.
  • Selectively permeable membranes surrounding an osmotically active driving complex are also suitable for orally administered compositions of the invention.
  • fluid from the environment surrounding the capsule is imbibed by the driving complex, which swells to displace the agent or agent composition through an aperture.
  • delivery platforms can provide an essentially zero order delivery profile as opposed to the spiked profiles of immediate release formulations.
  • a time-delay material such as glycerol monostearate or glycerol stearate can also be used.
  • Oral compositions can include standard carriers such as mannitol, lactose, starch, magnesium stearate, sodium saccharine, cellulose, magnesium carbonate, etc. Such carriers are preferably of pharmaceutical grade.
  • compositions of the invention can be intended for topical administration, in which case the carrier can be in the form of a solution, emulsion, ointment or gel base.
  • the base for example, can comprise one or more of the following: petrolatum, lanolin, polyethylene glycols, beeswax, mineral oil, diluents such as water and alcohol, and emulsifiers and stabilizers.
  • Thickening agents can be present in a composition for topical administration. If intended for transdermal administration, the composition can be in the form of a transdermal patch or an iontophoresis device.
  • Topical formulations can comprise a concentration of a compound of the invention of from between 0.01% and 10% w/v (weight per unit volume of composition).
  • the compositions can include various materials that modify the physical form of a solid or liquid dosage unit.
  • the composition can include materials that form a coating shell around the active ingredients.
  • the materials that form the coating shell are typically inert, and can be selected from, for example, sugar, shellac, and other enteric coating agents.
  • the active ingredients can be encased in a gelatin capsule.
  • the compositions can consist of gaseous dosage units, e.g., it can be in the form of an aerosol.
  • aerosol is used to denote a variety of systems ranging from those of colloidal nature to systems consisting of pressurized packages. Delivery can be by a liquefied or compressed gas or by a suitable pump system that dispenses the active ingredients. Aerosols of the compositions can be delivered in single phase, bi-phasic, or tri- phasic systems in order to deliver the composition. Delivery of the aerosol includes the necessary container, activators, valves, subcontainers, Spacers and the like, which together can form a kit. Preferred aerosols can be determined by one skilled in the art, without undue experimentation.
  • compositions of the present invention can comprise an additional therapeutically active agent selected from among those including, but not limited to, an additional anticancer agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anti-depressant and an analgesic agent.
  • additional anticancer agent selected from among those including, but not limited to, an additional anticancer agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anti-depressant and an analgesic agent.
  • an additional therapeutically active agent selected from among those including, but not limited to, an additional anticancer agent, an antiemetic agent, a hematopoietic colony stimulating factor, an anti-depressant and an analgesic agent.
  • the pharmaceutical compositions can be prepared using methodology well known in the pharmaceutical art. For example, a composition intended to be administered by injection can be prepared by combining a compound of the invention with water to form a solution. A surfactant can be added to facilitate the formation of a homogen
  • the pharmaceutical compositions of the present invention may comprise one or more known therapeutically active agents.
  • the pharmaceutical compositions of the present invention can be administered prior to, at the same time as, or after an additional anticancer agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other.
  • the pharmaceutical compositions of the present invention can be administered prior to, at the same time as, or after an antiemetic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the pharmaceutical compositions of the present invention can be administered prior to, at the same time as, or after a hematopoietic colony stimulating factor, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours, 72 hours, 1 week, 2 weeks, 3 weeks or 4 weeks of each other.
  • the pharmaceutical compositions of the present invention can be administered prior to, at the same time as, or after an opioid or non-opioid analgesic agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • the pharmaceutical compositions of the present invention can be administered prior to, at the same time as, or after an anti-depressant agent, or on the same day, or within 1 hour, 2 hours, 12 hours, 24 hours, 48 hours or 72 hours of each other.
  • KITS [0142] The invention encompasses kits that can simplify the administration of a compound or composition of the invention to a subject.
  • a typical kit of the invention comprises a unit dosage of a compound of the invention.
  • the unit dosage form is in a container, which can be sterile, containing an effective amount of a compound of the invention and a pharmaceutically acceptable carrier or vehicle.
  • the unit dosage form is in a container containing an effective amount of a compound of the invention as a lyophilate.
  • the kit can further comprise a second container which contains a solution useful for the reconstitution of the lyophilate, such as saline or phosphate buffered saline.
  • the kit can also comprise a label or printed instructions for use of a compound of the invention.
  • the kit can further comprise a unit dosage form of another therapeutically active agent.
  • the kit comprises a container containing an amount of an additional anticancer agent effective to treat cancer.
  • the kit comprises a container containing a therapeutically active agent such as an antiemetic agent, a hematopoietic colony- stimulating factor, an analgesic agent or an anxiolytic agent.
  • the kit comprises a unit dosage form of a pharmaceutical composition of the invention.
  • Kits of the invention can further comprise a device that is useful for administering the unit dosage forms of a compound or pharmaceutical composition of the invention. Examples of such devices include, but are not limited to, a syringe, a drip bag, a patch or an enema, which optionally contain the unit dosage forms.
  • Cancer or a neoplastic disease including, but not limited to, neoplasms, tumors, metastases, or any disease or disorder characterized by uncontrolled cell growth, can be treated or prevented by administration of an amount of a compound of the invention effective to treat cancer or by administration of an amount of a composition effective to treat cancer, said composition comprising a pharmaceutically acceptable carrier and a compound of the invention.
  • the compound of the invention is a peptide platinum complex
  • the compositions can comprise a pharmaceutically acceptable salt thereof.
  • treating as it applies to cancer encompasses both the treatment and/or prevention of cancer or neoplastic disease as described herein.
  • Animal models of cancer are used to test PT complexes according to the invention for an in vivo effect on cancer.
  • Mouse models are useful for such in vivo testing and include the following mouse models, without limitation. Adams JM, Harris AW, Pinkert CA, Corcoran LM, Alexander WS, Cory S, Palmiter RD, Brinster RL.1985.
  • the c-myc oncogene driven by immunoglobulin enhancers induces lymphoid malignancy in transgenic mice. Nature 318: 533–538.
  • Bishop JM.1985a Exploring carcinogenesis with retroviral and cellular oncogenes. Progress Med Virol 32: 5–14. Bishop JM.1985b.
  • a murine lung cancer co-clinical trial identifies genetic modifiers of therapeutic response. Nature 483: 613–617. Costantini F, Lacy E.1981. Introduction of a rabbit -globin gene into the mouse germ line. Nature 294: 92–94. de The H, Lavau C, Marchio A, Chomienne C, Degos L, Dejean A.1991. The PML-RARcx fusion mRNA generated by the t(15;17) translocation in acute promyelocytic leukemia encodes a functionally altered RAR. Cell 66: 675–684. Doetschman T, Gregg RG, Maeda N, Hooper ML, Melton DW, Thompson S, Smithies O.1987.
  • Histone deacetylase inhibitors induce remission in transgenic models of therapy-resistant acute pro-myelocytic leukemia. J Clin Invest 108: 1321–1330. Jacks T, Fazeli A, Schmitt EM, Bronson RT, Goodell MA, Weinberg RA.1992. Effects of an Rb mutation in the mouse. Nature 359: 295–300. Jaenisch R.1976. Germ line integration and Mendelian transmission of the exogenous Moloney leukemia virus. Proc Natl Acad Sci 73: 1260–1264. Jaenisch R, Mintz B.1974. Simian virus 40 DNA sequences in DNA of healthy adult mice derived from preimplantation blastocysts injected with viral DNA.
  • Chromosomal translocation t(15;17) in human acute promyelocytic leukemia fuses RARcx with a novel putative transcription factor, PML.
  • Kinkade CW Castillo-Martin M, Puzio-Kuter A, Yan J, Foster TH, Gao H, Sun Y, Ouyang X, Gerald WL, Cordon-Cardo C, et al.2008.
  • Targeting AKT/mTOR and ERK MAPK signaling inhibits hormone-refractory prostate cancer in a preclinical mouse model. J Clin Invest 118: 3051– 3064.
  • p53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362: 847–849. Lunardi A, Ala U, Epping MT, Salmena L, Webster KA, Wang G, Mazzuc-chelli R, Stack E, Lis R, Patnaik A, et al.2013. A co-clinical approach identifies mechanisms and potential therapies for androgen deprivation resistance in prostate cancer. Nat Genet 45: 747– 755. Martin GR.1981. Isolation of a pluripotent cell line from early mouse embryos cultured in medium conditioned by teratocarcinoma stem cells. Proc Natl Acad Sci 78: 7634– 7638.
  • Palmiter RD Brinster RL.1985. Transgenic mice. Cell 41: 343–345.
  • the present invention provides methods for treating cancer, including: killing a cancer cell or neoplastic cell; inhibiting the growth of a cancer cell or neoplastic cell; inhibiting the replication of a cancer cell or neoplastic cell; or ameliorating a symptom thereof, said methods comprising administering to a subject in need thereof an amount of a compound of the invention effective to treat cancer.
  • the compounds of the invention can be used accordingly in a variety of settings for the treatment of various cancers.
  • a peptide platinum complex of the invention can enter a cell by diffusion and react with DNA to form inter-strand and intra-strand cross-links and DNA-protein crosslinks, which can interfere with the ability of the cell to replicate.
  • the subject in need of treatment has previously undergone treatment for cancer. Such previous treatments include, but are not limited to, prior chemotherapy, radiation therapy, surgery or immunotherapy, such as cancer vaccines.
  • the cancer being treated is a cancer which has demonstrated sensitivity to platinum therapy or is known to be responsive to platinum therapy.
  • cancers include, but are not limited to, small-cell lung cancer, non-small cell lung cancer, ovarian cancer, breast cancer, bladder cancer, testicular cancer, head and neck cancer, colorectal cancer, Hodgkin’s disease, leukemia, osteogenic sarcoma, and melanoma.
  • the cancer being treated is a cancer which has demonstrated resistance to platinum therapy or is known to be refractory to platinum therapy.
  • refractory cancers include, but are not limited to, cancers of the cervix, prostate, and esophagus.
  • a cancer may be determined to be refractory to a therapy when at least some significant portion of the cancer cells are not killed, or their cell division are not arrested in response to the therapy.
  • a cancer is refractory where the number of cancer cells has not been significantly reduced or has increased.
  • cancers include, but are not limited to, cancers of the cervix, prostate, and esophagus.
  • Other cancers that can be treated with the compounds of the invention include, but are not limited to, cancers disclosed below in Table 3 and metastases thereof. TABLE 3
  • the cancer is selected from the group consisting of pancreatic cancer, colorectal cancer, mesothelioma, a malignant pleural effusion, peritoneal carcinomatosis, peritoneal sarcomatosis, renal cell carcinoma, small cell lung cancer, non- small cell lung cancer, testicular cancer, bladder cancer, breast cancer, head and neck cancer, and ovarian cancer.
  • the cancer is renal cell carcinoma, pancreatic cancer, colorectal cancer or mesothelioma.
  • PROPHYLACTIC METHODS The compounds of the invention can also be administered to prevent progression to a neoplastic or malignant state, including but not limited to the cancers listed in Table 1. Such prophylactic use is indicated in conditions known or suspected of preceding progression to neoplasia or cancer, in particular, where non-neoplastic cell growth consisting of hyperplasia, metaplasia, or most particularly, dysplasia has occurred (for review of such abnormal growth conditions, see Robbins and Angell, 1976, Basic Pathology, 2d Ed., W.B. Saunders Co., Philadelphia, pp.68-79.).
  • Hyperplasia is a form of controlled cell proliferation involving an increase in cell number in a tissue or organ, without significant alteration in structure or function. For example, endometrial hyperplasia often precedes endometrial cancer and precancerous colon polyps often transform into cancerous lesions. Metaplasia is a form of controlled cell growth in which one type of adult or fully differentiated cell substitutes for another type of adult cell. Metaplasia can occur in epithelial or connective tissue cells. A typical metaplasia involves a somewhat disorderly metaplastic epithelium.
  • Dysplasia is frequently a forerunner of cancer, and is found mainly in the epithelia; it is the most disorderly form of non-neoplastic cell growth, involving a loss in individual cell uniformity and in the architectural orientation of cells.
  • Dysplastic cells often have abnormally large, deeply stained nuclei, and exhibit pleomorphism.
  • Dysplasia characteristically occurs where there exists chronic irritation or inflammation, and is often found in the cervix, respiratory passages, oral cavity, and gall bladder.
  • the presence of one or more characteristics of a transformed phenotype, or of a malignant phenotype, displayed in vivo or displayed in vitro by a cell sample from a patient can indicate the desirability of prophylactic/therapeutic administration of the composition of the invention.
  • characteristics of a transformed phenotype include morphology changes, looser substratum attachment, loss of contact inhibition, loss of anchorage dependence, protease release, increased sugar transport, decreased serum requirement, expression of fetal antigens, disappearance of the 250,000 dalton cell surface protein, etc.
  • leukoplakia a benign-appearing hyperplastic or dysplastic lesion of the epithelium, or Bowen's disease, a carcinoma in situ
  • fibrocystic disease is indicative of the desirability of prophylactic intervention.
  • the prophylactic use of the compounds of the invention is also indicated in some viral infections that may lead to cancer.
  • human papilloma virus can lead to cervical cancer (see, e.g., Hernandez-Avila et al., Archives of Medical Research (1997) 28:265-271)
  • Epstein-Barr virus (EBV) can lead to lymphoma (see, e.g., Herrmann et al., J Pathol (2003) 199(2):140-5)
  • hepatitis B or C virus can lead to liver carcinoma (see, e.g., El- Serag, J Clin Gastroenterol (2002) 35(5 Suppl 2):S72-8)
  • human T cell leukemia virus (HTLV)-I can lead to T-cell leukemia (see e.g., Mortreux et al., Leukemia (2003) 17(1):26- 38)
  • human herpesvirus-8 infection can lead to Kaposi’s sarcoma (see, e.g., Kadow
  • a patient which exhibits one or more of the following predisposing factors for malignancy can treated by administration of an effective amount of a compound of the invention: a chromosomal translocation associated with a malignancy (e.g., the Philadelphia chromosome for chronic myelogenous leukemia, t(14;18) for follicular lymphoma, etc.), familial polyposis or Gardner's syndrome (possible forerunners of colon cancer), benign monoclonal gammopathy (a possible forerunner of multiple myeloma), a first degree kinship with persons having a cancer or precancerous disease showing a Mendelian (genetic) inheritance pattern (e.g., familial polyposis of the colon, Gardner's syndrome, hereditary exostosis, polyendocrine adenomatosis, medullary thyroid carcinoma with amyloid production and pheochromocytoma, Peutz-Jeghers syndrome, neurode chromosomal translocation
  • a composition of the invention is administered to a human patient to prevent progression to breast, colon, ovarian, or cervical cancer.
  • MULTI-MODALITY THERAPY FOR CANCER [0163]
  • the compounds of the invention can be administered to a subject that has undergone or is currently undergoing one or more additional anticancer treatment modalities including, but not limited to, surgery, radiation therapy, or immunotherapy, such as cancer vaccines.
  • the invention provides methods for treating cancer comprising (a) administering to a subject in need thereof an amount of a compound of the invention effective to treat cancer; and (b) administering to said subject one or more additional anticancer treatment modalities including, but not limited to, surgery, radiation therapy, or immunotherapy, such as a cancer vaccine.
  • the additional anticancer treatment modality is radiation therapy.
  • the additional anticancer treatment modality is surgery.
  • the additional anticancer treatment modality is immunotherapy.
  • the compound of the invention is administered concurrently with radiation therapy.
  • the additional anticancer treatment modality is administered prior or subsequent to administration of a compound of the invention, preferably at least an hour, five hours, 12 hours, a day, a week, a month, more preferably several months (e.g., up to three months), prior or subsequent to administration of a compound of the invention.
  • any radiation therapy protocol can be used depending upon the type of cancer to be treated.
  • x-ray radiation can be administered; in particular, high-energy megavoltage (radiation of greater that 1 MeV energy) can be used for deep tumors, and electron beam and orthovoltage x-ray radiation can be used for skin cancers.
  • the invention provides methods of treatment of cancer with a compound of the invention as an alternative to chemotherapy or radiation therapy where the chemotherapy or the radiation therapy has proven or can prove too toxic, e.g., results in unacceptable or unbearable side effects, for the subject being treated.
  • the subject being treated can, optionally, be treated with another anticancer treatment modality such as surgery, radiation therapy or immunotherapy, depending on which treatment is found to be acceptable or bearable.
  • the compounds of the invention can also be used in an in vitro or ex vivo fashion, such as for the treatment of certain cancers, including, but not limited to leukemias and lymphomas, such treatment involving autologous stem cell transplants.
  • This can involve a multi-step process in which the animal’s autologous hematopoietic stem cells are harvested and purged of all cancer cells, the patient’s remaining bone-marrow cell population is then eradicated via the administration of a high dose of a compound of the invention with or without additional anticancer agents and/or high dose radiation therapy, and the stem cell graft is infused back into the animal. Supportive care is then provided while bone marrow function is restored and the subject recovers.
  • the present invention also provides methods for treating cancer comprising administering to a subject in need thereof an amount of a compound of the invention effective to treat cancer and one or more additional anticancer agents or pharmaceutically acceptable salts thereof, said additional anticancer agents not being compounds of the invention.
  • the combination of agents can act additive or synergistic.
  • Suitable additional anticancer agents include, but are not limited to, gemcitabine, capecitabine, methotrexate, taxol, taxotere, mercaptopurine, thioguanine, hydroxyurea, cytarabine, cyclophosphamide, ifosfamide, nitrosoureas, cisplatin, carboplatin, mitomycin, dacarbazine, procarbizine, etoposide, teniposide, campathecins, bleomycin, doxorubicin, idarubicin, daunorubicin, dactinomycin, plicamycin, mitoxantrone, L-asparaginase, doxorubicin, epirubicin, 5-fluorouracil (5- fluorouracil), taxanes such as docetaxel and paclitaxel, leucovorin, levamisole, irinotecan, estramustine,
  • the additional anticancer agent can be, but is not limited to, a drug listed in Table 4.
  • Additional anticancer agents that can be used in the compositions and methods of the present invention include, but are not limited to: acivicin; aclarubicin; acodazole hydrochloride; acronine; adozelesin; aldesleukin; altretamine; ambomycin; ametantrone acetate; aminoglutethimide; amsacrine; anastrozole; anthramycin; asparaginase; asperlin; azacitidine; azetepa; azotomycin; batimastat; benzodepa; bicalutamide; bisantrene hydrochloride; bisnafide dimesylate; bizelesin; bleomycin sulfate; brequinar sodium; bropirimine; busulfan; cactinomycin;
  • anticancer drugs include, but are not limited to: 20-epi- 1,25 dihydroxyvitamin D3; 5-ethynyluracil; abiraterone; aclarubicin; acylfulvene; adecypenol; adozelesin; aldesleukin; ALL-TK antagonists; altretamine; ambamustine; amidox; amifostine; aminolevulinic acid; amrubicin; amsacrine; anagrelide; anastrozole; andrographolide; angiogenesis inhibitors; antagonist D; antagonist G; antarelix; anti- dorsalizing morphogenetic protein-1; antiandrogen, prostatic carcinoma; antiestrogen; antineoplaston; antisense oligonucleotides; aphidicolin glycinate; apoptosis gene modulators; apoptosis regulators; apurinic acid; ara-C
  • the additional anticancer agent is gemcitabine, capecitabine or 5-fluorouracil.
  • OTHER THERAPEUTIC AGENTS can further comprise the administration of a compound of the invention and another therapeutically active agent or pharmaceutically acceptable salt thereof.
  • the compound of the invention and the therapeutically active agent can act additively or, more preferably, synergistically.
  • a compound of the invention is administered concurrently with the administration of one or more other therapeutically active agents, which can be part of the same composition or in a different composition from that comprising the compound of the invention.
  • a compound of the invention is administered prior to or subsequent to administration of one or more other therapeutically active agents.
  • Kits comprising a compound of the invention, preferably purified, and one or more therapeutically active agents, in one or more containers are also provided.
  • the other therapeutically active agent can be an antiemetic agent.
  • Suitable antiemetic agents include, but are not limited to, metoclopromide, domperidone, prochlorperazine, promethazine, chlorpromazine, trimethobenzamide, ondansetron, granisetron, hydroxyzine, acethylleucine monoethanolamine, alizapride, azasetron, benzquinamide, bietanautine, bromopride, buclizine, clebopride, cyclizine, dimenhydrinate, diphenidol, dolasetron, meclizine, methallatal, metopimazine, nabilone, oxyperndyl, pipamazine, scopolamine, sulpiride, tetrahydro
  • the antiemetic agent is granisetron or ondansetron.
  • the other therapeutically active agent can be an hematopoietic colony stimulating factor. Suitable hematopoietic colony stimulating factors include, but are not limited to, filgrastim, sargramostim, molgramostim and epoietin alfa.
  • the other therapeutically active agent can be an opioid or non-opioid analgesic agent.
  • Suitable opioid analgesic agents include, but are not limited to, morphine, heroin, hydromorphone, hydrocodone, oxymorphone, oxycodone, metopon, apomorphine, normorphine, etorphine, buprenorphine, meperidine, lopermide, anileridine, ethoheptazine, piminidine, betaprodine, diphenoxylate, fentanil, sufentanil, alfentanil, remifentanil, levorphanol, dextromethorphan, phenazocine, pentazocine, cyclazocine, methadone, isomethadone and propoxyphene.
  • Suitable non-opioid analgesic agents include, but are not limited to, aspirin, celecoxib, rofecoxib, diclofinac, diflusinal, etodolac, fenoprofen, flurbiprofen, ibuprofen, ketoprofen, indomethacin, ketorolac, meclofenamate, mefanamic acid, nabumetone, naproxen, piroxicam and sulindac.
  • the other therapeutically active agent can be an anxiolytic agent.
  • Suitable anxiolytic agents include, but are not limited to, buspirone, and benzodiazepines such as diazepam, lorazepam, oxazapam, chlorazepate, clonazepam, chlordiazepoxide and alprazolam.
  • EXAMPLE 1 SYNTHESIS CIS-[TRANS -(1R,2R)-1,2-DIAMINO- CYCLOHEXANE]DIODOPLATINUM(II), (10) [0183] A filtered solution of K 2 PtCl 4 (12.51g, 30.14 mmol) (Alfa Aesar, Ward Hill, MA; or equivalent)) in water (100 mL) was added to a solution of KI (29.19 g, 176 mmol) in water (500 mL) at 25°C and stirred for 10 min.
  • the solids were re-suspended in dimethylformamide (DMF) (150 mL) and filtered. The filter cake was then washed with DMF (3 mL), water (3 ⁇ 100 mL) and acetone (3 ⁇ 7 mL). The solids were collected and dried under reduced pressure to provide cis-[trans-(1R,2R)-1,2-diaminocyclohexane] diiodoplatinum(II) (10) as a light yellow powder (15.28g, 90% ).
  • DMF dimethylformamide
  • EXAMPLE 2 PREPARATION OF DIAMINOCYCLOHAXANE-CARBONATO PLATINATE (II) (15) [A NOVEL PLATINUM COMPOUND] [0184] To DACHPtCl 2 (23.602 mg; 62.08 ⁇ mol) or DACHPtI 2 (35.0 mg; 62.08 ⁇ mol) ([diaminocyclohexane]diiodoplatinum(II)) in Water (0.5 mL), Ag 2 SO 4 (19.374 mg; 62.14 ⁇ mol) was added as a solution in 0.5 mL of Water, sonicated and then stirred for 24h.
  • EXAMPLE 3 PEPTIDE SYNTHESIS: ACGPSRVGGCNH2, SILVER SALT, (12) [0186] To AcGPSRVGGCNH 2 HCl (SEQ ID NO: 145) (23.602 mg; 12.176 ⁇ mol) Water (0.5 mL) was added and material was dissolved.1N HCl solution (1 mL) was added subsequently and the solution was mixed thoroughly. After 20 min. the solution was evaporated in a stream of Nitrogen, and the resulting residue was dried in vacuo for 24 h.
  • the lipid vesicles containing Pt complexes can be extruded by passage through a thin needle or membrane under pressure, for small scale preparations, or else fluidized using an appropriate microfluidizer, for larger scale preparations.
  • either monosaccharides (sorbitol or mannitol) at 5% (W:W) concentration or disaccharides (trehalose, sucrose,..) at 10% (W:W) can be added can be added to the platinum complexes encapsulated into liposomes.
  • W:W monosaccharides
  • disaccharides trehalose, sucrose,..
  • W:W disaccharides
  • EXAMPLE 5 ENCAPSULATION of DIAMINOCYCLOHAXANE CARBONATO PLATINATE (II) (15), PLATINUM COMPOUNDS AND PLATINUM-PEPTIDE COMJUGATES IN PLGA NANOPARTICLES [0190] Weigh 100 mg (+/- 5 mg) of poly(lactic-co-glycolic acid) (PLGA) and place into a glass test tube. Add 1 ml of solvent (ethyl acetate (EtAc) or dichloromethane (DCM)) to the PLGA. Cover the top of the tube and let the polymer dissolve overnight, adding additional solvent the next day upon any evaporation.
  • solvent ethyl acetate (EtAc) or dichloromethane (DCM)
  • EXAMPLE 6 ENCAPSULATION of DIAMINOCYCLOHAXANE CARBONATO PLATINATE (II) (15), OTHER PLATINUM COMPOUNDS AND PLATINUM- PEPTIDE CONJUGATES IN VIRAL PARTICLES [0195]
  • AAV or other type virus particles at ca 1x10 14 vp/mL preparation onto a PD-10 desalting column, equilibrated with buffer containing 5mM reducing agent (2-mercaptoethanol or dithiothreitol), 1mM EDTA and 25 mM sodium bicarbonate at pH 9.0.
  • Collect the exclusion volume containing the partially dissociated viral particles and hold for several hours at room temperature to fully dissociate particles into the comprising viral proteins.
  • To re-associate proteins into particles apply the solution onto another PD10 equilibrated with 1mM CaCl2/100mM NaCl and 10mMTris pH 7.0 and collect exclusion volume.
  • To the collected volume add 50-100mg od platinum compound and allow particle to reform at room temperature.
  • EXAMPLE 7 IN VITRO TESTING FOR ANTICANCER ACTIVITY IN HUMAN AND MURINE CELLS [0196] The following tests can be used to assess the in vitro anticancer activity of solutions of Pt complexes in human and murine cell lines [0197] A solution of a Pt complex is added to human tumor cell lines (HT 29, B16, and PACA2) or murine tumor cell lines (L1210, CT26) cultured in 96-well plates. After 18 hours of incubation, the cells are pulsed with 3H thymidine and washed with phosphate-buffered saline (PBS).
  • PBS phosphate-buffered saline
  • the amount of radioisotope incorporation is measured and used to calculate the effective concentration 50 (EC50), which is the concentration that causes a 50% decrease in cell proliferation.
  • EC50 effective concentration 50
  • the test protocol for the L1210 model is described in Han et al., Cancer Chemother. Pharmacol.39: 17-24 (1996).
  • (0165) cells are pulsed with 3H-Thy.
  • the amount of isotope incorporation is measured and used to calculate the EC50, which is the concentration that causes a 50% decrease in cell proliferation.
  • a Pt complex having an EC50 of ⁇ 100 ⁇ M possesses sufficient activity to be considered useful according to the invention.
  • a Pt complex which does not achieve a 50% decrease in cell proliferation at any concentration is not an anticancer compound according to the invention.
  • A375 cells human skin melanoma derived cell line
  • the cell density is adjusted, and cell suspension transferred to the assay multi-well plate.
  • the marginal wells are filled with PBS.
  • the assay plate is incubated in a cell incubator for about 16 ⁇ 18 hours.
  • Working solutions of test compounds and positive control at various concentrations are added to corresponding wells of the plate.
  • the assay plate is then incubated for an additional 72 hours in a 37°C/ 5% CO 2 incubator. After incubation, the working solution of CellTiter-Glo® reagent is added to the corresponding wells and shaken on an orbital shaker.
  • the assay plate is incubated at room temperature for a short while to stabilize the luminescent signal.
  • Luminescence signals are measured by a luminescence plate reader, such as PheraStar (BMG). Data are stored on a local computer or computer server for analysis.
  • Cell killing results obtained with some of peptide platinum complexes in combination with the A375 cell line are provided in Figures 1, 2 and 3 for Onco-001, 003 and 005, respectively, as shown above and Figure 4 for doxorubicin, as a control using BEL-7402 cells.
  • Onco- 001 was the least potent with an EC50 of ca.130 ⁇ M; whereas, both Onco-003 and Onco-005 displayed EC50 values of less than 10 ⁇ M, indicating that Onco-003 and Onco -005 are approximately 15X more potent than Onco-001.
  • An inactive compound is one that displays minimal or no killing activity at any concentration, even as high as at a concentration of 10- 50mM.
  • EXAMPLE 8 TREATMENT USING A MOUSE MODEL OF CANCER [0200]
  • the present invention also provides methods for treating cancer comprising administering to a subject in need thereof an amount of a compound of the invention effective to treat cancer and one or more additional anticancer agents or pharmaceutically acceptable salts thereof.
  • Melanoma [0201]
  • a peptide platinum complex according to the invention is administered to a mammal, and after a sufficient time, the effect of the complex on cancer in vivo is determined according to any parameters selected by a person of ordinary skill in the art.
  • a peptide platinum complex such as Diaminocyclohaxane-Carbonato Platinate (II)- AcGPSRVGGCNH2 (SEQ ID NO: 145), whether alone or encapsulated in lipid or PGLA particles is administered intravenously or subcutaneously to two cohorts (each cohort n ⁇ 10) of xenograft transplanted mice (xenograft transplant model) for which the xenograft implant in nude mice would be human melanoma cell lines such as A-2058 or A357.
  • the two cohorts one is the control arm and the other is the treatment arm.
  • mice After implant, the tumors are allowed to grow to 50 to 100mm 3 , subsequently the control cohort is administered saline and the treatment cohort is administered drug at the appropriate dose. The mice are monitored for the next 3-4 weeks, monitoring and measuring tumor size. Other mice models can also be used, these models would include syngeneic transplant models such as the B16 melanoma model or genetically engineered mouse models for melanoma.
  • EXAMPLE 9 TREATMENT USING A MOUSE MODEL OF CANCER Breast Cancer [0202] A similar approach to melanoma can be used for in-vivo testing of the peptide platinum complexes for breast cancer.
  • the platinum complex would be comprised of the platinum core structure, dicyclohexylamino-platinum, complexed with the one of the breast cancer homing peptides, such as WX 1 APAYQRFLX 2 , (SEQ ID NO: 150), where X 1 is any amino acid, except for W and C, and X2 is gamma-carboxyglutamic acid, and also, the N- terminal amine is acylated.
  • WX 1 APAYQRFLX 2 SEQ ID NO: 150
  • X 1 is any amino acid, except for W and C
  • X2 is gamma-carboxyglutamic acid
  • the N- terminal amine is acylated.
  • Different mouse models can be applied including xenograft implant, syngeneic transplant and genetically engineered mouse model.

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